Interaction of drug- and granulocyte-mediated killing of Pseudomonas aeruginosa in a murine pneumonia model.

Institute for Therapeutic Innovation, Department of Medicine, College of Medicine, University of Florida Research and Academic Center, Lake Nona.

2

Achaogen, San Francisco, California.

Abstract

BACKGROUND:

Killing of bacterial pathogens by granulocytes is a saturable process, as previously demonstrated. There is virtually no quantitative information about how granulocytes interact with antimicrobial chemotherapy to kill bacterial cells.

METHODS:

We performed a dose-ranging study with the aminoglycoside plazomicin against Pseudomonas aeruginosa ATCC27853 in a granulocyte-replete murine pneumonia model. Plazomicin was administered in a humanized fashion (ie, administration of decrementing doses 5 times over 24 hours, mimicking a human daily administration profile). Pharmacokinetic profiling was performed in plasma and epithelial lining fluid. All samples were simultaneously analyzed with a population model. Mouse cohorts were treated for 24 hours; other cohorts treated with the same therapy were observed for another 24 hours after therapy cessation, allowing delineation of the therapeutic effect necessary to reduce the bacterial burden to a level below the half-saturation point.

CONCLUSIONS:

For patients with large bacterial burdens (eg, individuals with ventilator-requiring hospital-acquired pneumonia), it is imperative to kill ≥2 log10 CFU/g early after treatment initiation, to allow the granulocytes to contribute optimally to bacterial clearance.

Colony counts of Pseudomonas aeruginosa ATCC 27853 in the lungs of mice. Cohorts were euthanized at baseline (2 hours after challenge), at hour 26, and at hour 50. The difference between the data for 26 h and 50 h reflects the influence of granulocytes acting alone on the bacterial burden at hour 26. The untreated controls and the group treated with the lowest dose of plazomicin (5.5 mg/kg/d) were humanely euthanized at hour 26.